Our goal is to understand the contributions of white matter fiber pathways to high-level cognition, and the cognitive deficits associated with white matter damage in neurological disease. In this project, we will investigate how fiber pathway disconnection in focal brain injury due to stroke affects cognitive control abilities which serve to organize thoughts, perceptions and actions. Cognitive control deficits due to brain injury can have severe consequences for a patient's ability to carry out even simple tasks. Clinical and scientific investigations of the neual basis of cognitive control have mainly focused on cortical gray matter, leaving a gap in our understanding of the role of white matter fiber pathways and the consequences of their disruption. We will address this gap with focal lesion evidence on the white matter substrates of cognitive control. To execute the goals of the current study, we will acquire high angular resolution diffusion imaging (HARDI), resting-state functional magnetic resonance imaging (RS-fMRI) and high-resolution structural MRI data from 90 chronic stroke patients with focal brain injury (45 left, 45 right hemisphere lesions) and 45 healthy controls. HARDI-based tractography will capture the extent of neurological damage to individual fiber pathways. Voxel- based morphometry (VBM) analysis of anatomical images will assess cortical involvement. Functional connectivity analysis of the RS-fMRI data will reveal how the interactions between distal cortical regions are affected by brain injury. Cognitive control abilities will be assessed with experimental, computerized tests. Cognitive tests will show how specific cognitive control functions, such as the ability to choose between conflicting actions or to alternate flexibly between multiple tasks, are affected by brain injury. The guiding hypothesis is that the integrity of fronto-posterior association fiber pathways is critical for cognitive control. Our first specifi aim is to investigate which fiber pathways are critical for specific cognitive control functions. W will correlate tractography-based measures of fiber integrity with cognitive test results to test a series of a priori predictions relating individual pathways with specific behavioral measures. For instance, we predict that damage to the left superior longitudinal fasciculus (SLF) will be associated with response selection deficits, and that the inferior occipital fasciculus (IOFF) damage will be associated with impaired control over verbal and spatial working memory. Our second specific aim is to assess the hypothesis that the behavioral effects of fronto-posterior fiber pathway damage can be dissociated from those of cortical gray matter loss. VBM will highlight the cortical regions critical for cognitive control, and regression analyses will assess the variance in behavioral deficits accounted for by fiber pathway and cortical damage. Our third specific aim will assess how fronto-posterior functional connectivity measures obtained from RS-fMRI data relate to behavioral deficits and the tractography-based structural connectivity measures. We will use statistical mediation analysis to examine the hypothesis that structural disconnections affect behavior because they alter the functional coupling between frontal and posterior cortical association areas. The combined use of HARDI and RS-fMRI to assess cognitive deficits and brain network dysfunction in a large group of focal lesion patients is the key distinguishing innovation of our project. Our team brings together expertise from multiple disciplines and extensive experience in using neuroimaging to study cognition in neurological disease. Our Center has a strong record in patient research and our VA facility has extensive patient recruitment and testing resources. We have used each of the techniques proposed here in our earlier investigations and have also collected new brain imaging data to establish the feasibility of our approach. Our findings will have theoretical impact, as there is a paucity of knowledge about white matter function. The outcome will be a rich set of novel brain imaging findings which will ultimately benefit the clinical diagnosis and treatment of survivors of stroke s well as other conditions that affect brain white matter.